In vivo positionable filtration devices and methods related thereto

ABSTRACT

In vivo positionable filtration devices are provided that filter one or more therapeutic agents in blood flowing in a blood vessel. The filtration devices include an elongated member and a filtering component coupled to the elongated member. The elongated member and the filtering component are dimensioned for positioning within a blood vessel of a human or non-human animal. Further, the filtering component includes a filtration material to filter the one or more therapeutic agents from blood. Methods of in vivo filtration of one or more therapeutic agents are also provided. The methods include positioning a filtration device in a blood vessel of a body of a human or non-human animal, and administering a therapeutic agent upstream from the target tissue site to direct flow of the therapeutic agent to the target tissue site and then to the filtration device. The filtration device is positioned downstream from a target tissue site.

CROSS-REFERENCE

This application is a continuation application of U.S. Nonprovisionalapplication Ser. No. 14/649,838, filed on Jun. 4, 2015, which is the 35U.S.C. § 371 national stage application of PCT Application No.PCT/US2013/076159, filed Dec. 18, 2013, which claims priority to U.S.Provisional Application Ser. No. 61/784,507, having the title “IN VIVOPOSITIONABLE FILTRATION DEVICES AND METHODS RELATED THERETO,” filed onMar. 14, 2013 and U.S. Provisional Application Ser. No. 61/745,183,having the title “IN VIVO POSITIONABLE FILTRATION DEVICES AND METHODSRELATED THERETO,” filed on Dec. 21, 2012, all of which are incorporatedherein by reference in their entirety

INTRODUCTION

In vivo positionable filtration devices are provided that filter one ormore therapeutic agents in blood flowing in a blood vessel. Thefiltration devices include an elongated member and a filtering componentcoupled to the elongated member. The elongated member and the filteringcomponent are dimensioned for positioning within a blood vessel of ahuman or non-human animal. Further, the filtering component includes afiltration material to filter the one or more therapeutic agents fromblood. Methods of in vivo filtration of one or more therapeutic agentsare also provided. The methods include positioning a filtration devicein a blood vessel of a body of a human or non-human animal, andadministering a therapeutic agent upstream from the target tissue siteto direct flow of the therapeutic agent to the target tissue site andthen to the filtration device. The filtration device is positioneddownstream from a target tissue site.

SUMMARY

In some aspects of the present disclosure, in vivo positionablefiltration devices are provided that filter one or more therapeuticagents in blood flowing in a blood vessel. The filtration devicesinclude an elongated member and a filtering component coupled to theelongated member. The elongated member and the filtering component aredimensioned for positioning within a blood vessel of a human ornon-human animal. Further, the filtering component includes a filtrationmaterial to filter the one or more therapeutic agents from blood.

In some aspects of the present disclosure, methods of in vivo filtrationof one or more therapeutic agents are provided. The methods includepositioning a filtration device in a blood vessel of a body of a humanor non-human animal, and administering a therapeutic agent upstream fromthe target tissue site to direct flow of the therapeutic agent to thetarget tissue site and then to the filtration device. The filtrationdevice is positioned downstream from a target tissue site. Further, thefiltration device is for filtering the therapeutic agent in the bloodflowing in the blood vessel. The in vivo positioned filtration devicefilters the therapeutic agent as the blood and the therapeutic agent arereceived by the filtration device.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a side view of an in vivo positionable filtrationdevice, according to one embodiment;

FIGS. 2A and 2B illustrate a close-up side view and a close-up topperspective view, respectively, of the filtration component shown inFIG. 1;

FIGS. 3-10 illustrate exemplary filtration devices according todifferent embodiments;

FIG. 11 illustrates an experimental model implementing a resin filterand Doxorubicin as a therapeutic agent, according to one embodiment;

FIG. 12 illustrates a graph of Doxorubicin kinetic curve for a resinresulting from experimental data obtained with the experimental modelshown in FIG. 11, according to one embodiment; and

FIG. 13 illustrates a graph of Doxorubicin kinetic curve for adsorbentresin resulting from experimental data obtained with the experimentalmodel shown in FIG. 11, according to one embodiment.

FIGS. 14A-14L illustrate various examples of positioned devices indifferent blood vessels.

DETAILED DESCRIPTION

Cancer is currently the second leading cause of death in the UnitedStates and is on course to exceed cardiovascular disease as the leadingcause of death in the next decade. Conventional intravenous chemotherapyis dose-limited by systemic toxicity. A common chemotherapeutic used fora variety of tumors is doxorubicin (Dox), whose toxicities include bonemarrow suppression, gastrointestinal damage, and perhaps mostnotoriously irreversible cardiac failure.

In order to limit these systemic toxicities and also further increasechemotherapeutic dose to the cancer, for certain tumors such as those inthe liver for instance, a chemotherapeutic agent such as Dox may beadministered intraarterially directly into the vessels feeding thetumor. However, large percentages of the chemotherapeutic agent may passdirectly through the tumor into the systemic venous circulation.

In some aspects, an in vivo positionable filtration device is providedto capture or otherwise filter therapeutic agents that pass through atarget tissue site (e.g., a cancerous site). The filtering of thetherapeutic agent may facilitate optimization of chemotherapy dosages,for example, and minimize systemic toxicity levels of thechemotherapeutic agent. While the devices and methods of the presentdisclosure are described with respect to cancer and chemotherapeuticagents, such as Dox, it should be appreciated that non-chemotherapeuticagents may also be applicable for cancerous and non-cancerousconditions, diseases, illnesses, etc.

Devices

In some aspects of the present disclosure, in vivo positionablefiltration devices are provided that filter one or more therapeuticagents in blood flowing in a blood vessel. The filtration devicesinclude an elongated member and a filtering component coupled to theelongated member. The elongated member and the filtering component aredimensioned for positioning within a blood vessel of a human ornon-human animal. Further, the filtering component includes a filtrationmaterial to filter the one or more therapeutic agents from blood.

The filtration material may include a material that filters one or moretherapeutic agents from the blood. The therapeutic agents may be, forexample, chemotherapeutic agents or non-chemotherapeutic agent may beimplemented. In one embodiment, the chemotherapeutic agent is Dox.

It should be appreciated that the term “therapeutic agent” is usedbroadly herein and may include therapeutic particles. Furthermore,references to “filtering of a therapeutic agent” are used broadly hereinand encompass the filtering of therapeutic particles. For example, incertain embodiments, particles may include free chemotherapy (ornon-chemotherapy) molecules, or chemotherapy (or non-chemotherapy)loaded molecules (e.g., chemotherapy molecules that are bound toparticles such as drug eluting resins or drug eluting activated carbon).Exemplary therapeutic agents include, but are not limited to:chemotherapy agents; vasoactive agents, e.g. verapamil, nicardipine, ormilrinone; Sodium tetradecyl sulfate (Sotradecol, Angiodynamics orBioNiche Pharmaceuticals); bleomycin; X-ray or MRI contrast agents;antibiotics; lytic agents (for example, and clot dissolving drugs suchas tPA). In certain embodiments, the particles may include blandparticles. Particles may include, for example, particles that occludeblood vessels of cancerous or otherwise diseased tissue. In someinstances, particles may include polymers, glues, resins, activatedcarbon, or glass. In certain embodiments, the particles may be bound toradiation emitting isotopes, such as radiotherapeutic particles.

The filtration material may include a material that has properties thatadsorb, bind, trap, or inactivate or degrade the therapeutic agent. Forinstance, in certain embodiments, the filtration material may includebeads or other particles that adsorb, bind, trap, or inactivate ordegrade the therapeutic agent.

As stated above, in certain embodiments, the filtration material mayfilter a therapeutic agent from the blood by adsorbing or binding to thetherapeutic agent to enable removal from the blood. For example, thefiltration material may possess properties that adsorb a therapeuticagent, chemically bind to a therapeutic agent, and/or magnetically bindto a magnetic carrier of the therapeutic agent, without significantbinding or filtration of endogenous entities in the blood. The bindingbetween the filtration material and the therapeutic agent may beirreversible or weakly reversible. In this way, the therapeutic agentmay be collected by the filtration material and removed from the blood.

The percentage of therapeutic agent removed may vary in differentembodiments based on the specific filtration material, therapeuticagent, and filtration device configuration. In certain embodiments, forexample, the percentage of therapeutic agent removed by the filtrationmaterial may range from 50% or greater, such as 80% or greater,including 95% or greater.

In one embodiment, the filtration material includes a resin that hasproperties that adsorbs a therapeutic agent, chemically binds to atherapeutic agent, and/or magnetically binds to a magnetic carrier boundto a therapeutic agent. Example filtration materials including resinshaving properties to adsorb and/or chemically bind to a therapeuticagent such as doxorubicin, may include, but are not limited to: strongacid cation exchange polymer resins; ion exchange resins; polymericadsorbent resins without ion exchange; resins including sulfonate groupsthat ionically bond to the therapeutic agent; chromatography basedresins, acrylic-based resins including those composed of polyacrylamide,polyacrylic acid, sodium acrylate and even vinyl copolymers, or anycombination thereof. Such resins could be incorporated onto a membraneor sheet made from polymers or cloth, with examples including Nafion(Dupont), Neosepta, CMI-7000 (Membranes International), and IONACmembranes (Sybron Chemicals).

For example, in one embodiment, a strong acid cation exchange polymerresins may be used for a mildly positively charged drug such as Dox.Other examples of compounds that chemically or physically (viaadsorption) bind to a therapeutic agent such as doxorubicin, mayinclude, but are not limited to: calsequestrin; cyclic oligosaccharides,such as cyclodextrins, including gamma-cyclodextrin; hNopp140;antibodies that specifically bind the agent, such as an anti-doxorubicinmonoclonal antibody (MAD 11); nucleolar phosphoprotein; Clostridiumbotulinum neurotoxin B; cell membrane lipids such as cardiolipin,phophatidylserine, and phosphatic acid; nucleic acid ligands so called‘aptamers’ including RNA and DNA; albumin; and hemoglobin.

Further, it should be appreciated that in other embodiments, variousother types of ion exchange resins may be applicable, including, but notlimited to, weak-acid cation exchange, weak-base anion exchange,strong-base anion exchange. For instance, in one embodiment, for anegatively charged drug (e.g., heparin), a strong-base anion exchangeresin is implemented.

Factors such as resin functional group and porosity/cross-linking,solution temperature, pH, concentration, and ionic strength may factorinto the effectiveness of the resin to bind to the therapeutic agent. Insome instances, for example, cyanogen bromide activation of resins maybe used to attach functional groups. In certain instances, a lowcross-linked version of these resins is implemented, such as 3% or less,including 2% or less. Higher cross-linked versions are also applicableand may also be implemented.

In certain embodiments, the filtration material includes carbon such asactivated carbon (e.g., charcoal or activated charcoal) that binds tothe therapeutic agent. The effectiveness of the activated carbon mayvary based on factors such as pore size, shape, surface area, ashcontent, and hardness, for example. In some instances, the carbon may becoated with additional resin material. Furthermore, carbons and resinsare inexpensive and small amounts may be used and still be effective.While larger amounts may be implemented in some instances, exampleamounts of carbons and resin, such as 10 grams or less, such as 5 gramsor less, and including 1 gram or less, may be implemented and beeffective.

Example resins for the filtration device may include, but are notlimited to, one or more of the following: HepaSphere, QuadraSphere,Dowex 50W-X2; Dowex 50W-X4; Dowex 50W-X8; Biorad AG50W-X2; BioradAG50W-X4; Biorad AG50W-X8; GE Sepharose Big Beads; Amberlite XAD-2;Tosoh Toyopearl MegaCap II; Purolite PAD 600; and Purolite CGC100X2.Example carbons for the filtration device may include, but are notlimited to, one or more of the following: Norit C Gran; Calgon TOG NDS20.times.50; and QUO-YC-1041.

In certain embodiments, the filtration material may include a materialthat improves biocompatibility, such as polymethyl-methacrylate (PMMA),chitosan, heparin, etc. In some instances, for example, the resin orcarbon of the filtration material may be coated or otherwise impregnatedwith the PMMA, chitosan, and/or heparin. Example coating methods may befound in U.S. Patent Publication No. 2010/0316694, the entirety of whichis incorporated herein by reference.

In certain embodiments, the filtration material may filter a therapeuticagent from the blood by inactivating or otherwise degrading thetherapeutic agent or the toxicity of the therapeutic agent. For example,the filtration material may be a catalytic material, such as animmobilized (covalently or non-covalently) enzyme that, for example,enzymatically degrades the therapeutic agent to reduce its toxicitylevel. Enzymatic degradation and inactivation of Dox, for example, mayoccur via cleavage of its sugar backbone with glycosidases contained inthe liver.

In other embodiments, the therapeutic agent administered to the patientmay be pretreated by covalently or non-covalently associating thecompound with a magnetic particle, such as a magnetic nanoparticle.Accordingly, the filtration material may be composed of a magneticmaterial so that following treatment the magnetically bound therapeuticparticle may be attracted to the magnetic material of the filtrationmaterial.

In yet other embodiments, the filtration material is composed of basicmechanical sieve-like filter which traps a wide range of particles thatare commonly used to embolize tumors, such as resin based particles,such as DC Beads and LC Beads (ion-exchange resins), QuadraSpheres andHepaSpheres (sodium acrylate and vinyl copolymer resin), EmboSpheres(tris-acryl resins), Bead Block and Cotonour Beads (polyvinyl alcoholresins), Onyx (ethylene vinyl copolymer, EVOH), TruFill or Histacryl(n-butyl-cyanoacrylate (nBCA) compounds), embolization coils, oractivated carbon particles. Such particles may or may not be loaded witha therapeutic agent that would elute in the tumor. In such exemplaryembodiments, the filtration material will trap these particles out ofthe exiting venous blood stream to prevent them from depositing innon-target organs. Moreover, the filtration material of such embodimentscould simultaneously be composed of a chemical based binding filtrationmechanism to filter out free drug from the blood as well.

The reduction of the toxicity level may vary based on the selectedfiltration material, therapeutic agent, and specific filtration deviceconfiguration. In certain embodiments, the reduction of toxicity levelranges from 50% or greater, such as 75% or greater, including 90% orgreater.

While parts of the present disclosure are described with respect to afiltration material having properties that either adsorb, bind, trap, orinactivate (or degrade) the therapeutic agent, it is appreciated that insome embodiments, the filtration material may include a combination ofthese properties. In some instances, for example, the filtrationmaterial may include one or more materials having properties thatadsorb, bind, trap, or inactivate (or degrade) the therapeutic agent.For example, parts of the present disclosure may be described withrespect to a filtration material including resin, carbon, or catalyticmaterial. It is appreciated that in some embodiments, the filtrationmaterial may include any combination of resin, carbon, and catalyticmaterials. Furthermore, the filtration material may include more thanone type of resin, carbon, or catalytic material. In some instances, forexample, the filtration material may include one or more materials thattrap particles, such as by mechanically trapping particles based on apore size of a filter being smaller than the size of the particle.

Still further, the filtration material may include a material to improvebiocompatibility, such as including but not limited to one or more ofthe following: PMMA, chitosan, heparin, citrate, andethylenediaminetetraacetic acid (EDTA). For example, the filtrationmaterial may include a resin coated with heparin and an activated carboncoated with chitosan. Moreover, the filtration material may beapplicable to more than one therapeutic agent—e.g., filter more than onechemotherapeutic agent, filter more than one non-chemotherapeutic agent,or filter a combination of chemotherapeutic and non-chemotherapeuticagents. For example, the filtration material may include a resin thatchemically binds to one chemotherapeutic agent and activated carbon thatbinds to another chemotherapeutic agent.

References may be made herein to a proximal and distal end of thefiltration device or components therein. The term “proximal” is usedhere to refer generally to the end or side of the filtration device orcomponent thereof that is closer to the operator of the device (e.g.,physician) than to the target tissue. The term “distal” is used here torefer generally to the end or side of the filtration device or componentthereof that is closer to the target tissue site than to the operator ofthe device.

In certain embodiments, the filtration device may be disposed within acatheter—e.g., with a filtering component disposed at the distal end ofthe catheter. The filtration device may include a frame structurecoupled to one or more membranes having filtration material disposedthereon or contained between multiple membrane layers. In someinstances, the filtration material may be disposed between multiplemembranes without being attached to the membrane, such as a slurrydisposed between multiple membranes. The catheter may be constructed ina variety of diameters that would fit the various sizes of bloodvessels. For example, small vein diameters, such as renal or hepaticveins, may include, but are not limited to, diameters betweenapproximately 8-14 mm; and large vein diameters, such as vena cave, mayinclude, but are not limited to diameters between approximately 20-30mm. The catheter would sheath, for example, the filtration device toenable endovascular delivery and retrieval of the filter device. Aportion of the filtration device inside the sheath may include theframing structure and membranes such that the framing structure andmembrane are displaced out the distal end of the sheath andconcentrically or eccentrically open along the target blood vessel wallduring positioning. In some instances, the membranes and the filtrationmaterial may be removable from the frame structure to enable thefiltration device to be removed and exchanged as many times as neededthrough a lumen of the catheter (e.g., central lumen, or other lumenwithin the catheter).

In certain embodiments, the filtration material may be disposed on oneor more porous membranes. For example, the filtration material may bedisposed between two or more porous membranes.

The porosity of the membrane may vary but should be sufficient to enableblood to pass through. In one embodiment, the porosity of the membranemay be selected based on the therapeutic agent particle size—e.g., tocapture therapeutic particles with a size larger than the pore size.Example pore sizes may include, but are not limited to pore sizes assmall as 40 microns to as large as 300 microns. Other pore sizes mayalso be implemented.

In certain embodiments, the filtering component is positioned at thedistal end of the filtration device. For example, the filteringcomponent may include the membranes and filtration material. Thefiltering component may also include a frame structure that the one ormore porous membranes are coupled thereto (e.g., adhered).

The frame structure may be expandable and constrainable to enable entryinto the blood vessel when constrained and to occlude the blood vesselwhen expanded. For example, the frame structure may be biased to anexpanded state when no outside force is applied, and constrained when anoutside force is applied, such as being drawn within the catheter. Theframe structure may have, for example, a wire mesh configuration that isconstrainable when drawn within the catheter. The frame structure may bemade from any variety of materials, such as, but not limited to, metals,metal alloys, polymeric materials, etc. For instance, in one embodiment,the material of the frame structure may include nitinol alloy. In someinstances, the material of the frame structure may include platinum orother higher atomic number metal beads or markers attached for increasedradiopacity to facilitate deployment and monitoring intraprocedurally.The frame structure, and the filtration device in general, may beconstructed to be non-thrombogenic without significant binding orfiltration of endogenous entities in the blood. In some instances, theframe structure may include a self-expanding configuration havinginterlocking joints, such as described in U.S. Pat. No. 5,800,517, theentirety of which is incorporated herein by reference.

In certain embodiments, the frame structure is concentrically oreccentrically positioned around the membrane and the filtrationmaterial. The filtration material may be disposed between the membraneand the outer frame structure for example. In other embodiments,multiple membranes may be coupled to the frame structure. The membranemay be flat in some instances, or folded or otherwise shaped to increasesurface area in other instances.

In certain embodiments, the membrane is porous to permit blood to passthrough and encounter the filtration material. The membrane may be madefrom a variety of materials but should enable blood to pass through.Example membrane materials may include, but are not limited to, fabrics,plastics, polymers, silicone, metals, metal alloys, etc. In certainembodiments, the membrane materials may themselves be composed of thefiltration material that has properties to adsorb, bind, trap,inactivate or degrade the therapeutic agent. For instance, the membranematerial may be impregnated with resin or carbon, or otherwise becomposed of a resin or carbon. In certain embodiments, the membrane issufficiently porous to permit the therapeutic agent to pass but filteredwhen contacting the filtration material.

The shape of the frame structure when expanded may vary, but shouldoccupy most if not all of the cross section of the blood vessel. Havingthe frame structure expand to the entire cross section of the bloodvessel may ensure the most amount of blood and therapeutic agent toenter the filtering component, and further may provide support orstability to retain the frame structure within the blood vessel. In someinstances, the frame structure has a generally circular cross shape suchas to conform to the generally circular cross shape of blood vessel. Insome instances, the frame structure is tapered, or otherwise decreasingin cross sectional area, from the distal end towards the proximal end.This may, for example, facilitate blood flow through the filteringcomponent while minimizing the amount of resistance to the flow ofblood.

The filtration device shown may also include an elongated control memberthat extends within the lumen of the catheter and operably coupled tothe frame structure. The elongated control member may, in someembodiments, enable an operator to displace the frame structure in andout of the distal end of the catheter to constrain and expand the framestructure, respectively. The elongated control member may also be usedby an operator to position the filtration device to the target locationwithin the blood vessel downstream from the target tissue site. In someinstances, more than one elongated control member may be implemented.

In certain embodiments, the filtration device is positioned within avein draining a target organ—e.g., an organ containing diseased orcancerous tissue—or a central vein. In some instances, for example, thefiltration device may be inserted within an internal jugular or femoralvein. The filtration device may be dimensioned and sufficientlymalleable to conform to walls of the vein, such as the renal vein,hepatic vein, vena cavae, or dural venous sinus.

In certain embodiments, the filtration device may include a removableand/or replaceable filtering component, or portion thereof. For example,the filtering component, or portion thereof, may be unique for any drugor variety of drug cocktails, both oncologic and non-oncologic, andremoved and exchanged for another filtering component, or portionthereof, for the same or different drug or drug cocktail. For instance,stroke patients receiving thrombolytic drugs intraarterially could alsogreatly benefit from filtration of such drugs.

FIG. 1 illustrates an in vivo positionable filtration device forfiltering a therapeutic agent in blood flowing in a blood vessel,according to one embodiment. Filtration device 100 includes catheter101, filtering component 102 disposed at the distal end of the catheter101, and handle 107 disposed at the proximal end of the catheter 101.The filtering component 102 includes a frame structure 103 coupled to amembrane 104 having filtration material 105 disposed thereon. FIGS. 2Aand 2B illustrate a close-up side view and close-up top perspectiveview, respectively, of the filtering component 102 shown in FIG. 1, andare described in conjunction with FIG. 1.

The frame structure 103 may be expandable and constrainable to enableentry into the blood vessel when constrained and enable occlusion of theblood vessel when expanded. For example, the frame structure 103 may bebiased to an expanded state when no outside force is applied, andconstrained when an outside force is applied, such as being drawn withinthe catheter. The frame structure 103 may have, for example, a wire meshconfiguration that is constrainable when drawn within the catheter 101.The frame structure 103 may be made from any variety of materials, suchas, but not limited to, metals, metal alloys, polymeric materials, etc.

In the embodiment shown, the frame structure 103 is concentricallypositioned around the membrane 104 and the filtration material 105. Thefiltration material 105 is disposed between the membrane 104 and theouter frame structure 103. In another embodiment, multiple membranes maybe coupled to the frame structure. For example, multiple membranes maybe positioned concentrically within the frame structure with thefiltration material disposed between both membranes. It should beunderstood that other variations of the relative placement of the framestructure, membranes, and filtration material may be implemented inother embodiments. For example, in one embodiment, a membrane may bemost interiorly positioned within the filtering component, and inanother embodiment, the filtration material may be most interiorlypositioned within the filtering component. In another embodiment, one ormore membranes and the filtration material may be disposedconcentrically around the frame structure.

In certain embodiments, the membrane 104 is porous to permit blood andtherapeutic agent to pass through and encounter the filtration material.The membrane may be made from a variety of materials but should enableblood to pass. In certain embodiment, the membrane has a pore size thatis larger than the therapeutic agent. In certain embodiments, themembrane has a pore size that is smaller than the therapeutic agent toprevent passage of the therapeutic agent past the filtering component.Example membrane materials may include, but are not limited to, fabrics,plastics, polymers, silicone, metals, metal alloys, etc. In certainembodiments, the membrane is made from a material with properties toadhere well to the filtration material.

It is appreciated that the frame structure may be porous and function asa membrane. In other embodiments, the filtration material may bedisposed on a porous frame structure, such as mesh or scaffolding,without an additional membrane coupled to the frame structure.

The shape of the frame structure when expanded may vary, but shouldoccupy most if not all of the cross section of the blood vessel. Havingthe frame structure expand to the entire cross section of the bloodvessel may ensure the most amount of blood and therapeutic agent enterthe receiving component, and further may provide support or stability toretain the frame structure within the blood vessel. In some instances,the frame structure has a generally circular cross shape such as toconform to the generally circular cross shape of blood vessel. In someinstances, the frame structure is tapered, or otherwise decreasing incross sectional area, from the distal end towards the proximal end—e.g.,to facilitate blood flow through the filtering component whileminimizing the amount of resistance to the flow of blood.

The filtration device shown in FIG. 1 also includes an elongated controlmember that extends within a lumen of the catheter and is operablycoupled to the frame structure. The elongated control member enables anoperator to displace the frame structure in and out of the distal end ofthe catheter to constrain and expand the frame structure, respectively.The elongated control member may also be used by an operator to positionthe filtration device to the target location within the blood vesseldownstream from the target tissue site. In one embodiment, the elongatedmember 106 is removably coupled to the frame structure 106 such that theelongated member.

FIGS. 3-10 illustrate exemplary filtration devices according todifferent embodiments. FIG. 3 illustrates an example filtration device,according to one embodiment. Filtration device 300 includes an elongatedcontrol member 307 that is operably coupled to a frame structure 303.Frame structure 303 is coupled to two porous membranes 304 a,304 b thathave filtration material 305 disposed between the two porous membranes304 a,304 b. In another embodiment, a single porous membrane composed ofthe filtration material 305 is disposed within the frame structure 303.The elongated control member 307 is operably coupled to the framestructure 303 and is used to displace the frame structure 305, porousmembranes 304 a,304 b, and filtration material 305 horizontally alongthe central axis of the catheter 301. The frame structure 303 is biasedto an expanded state so that when the frame structure 303 is displacedoutside the distal end of the catheter 301, as shown, the framestructure 303 is expanded to occupy the cross sectional area of theblood vessel 350. For example, x-ray fluoroscopy may be used to confirmthe tip. The frame structure 303 is constrainable such that when theframe structure 303 is drawn within the distal end of catheter 301, theframe structure 303 constrains to fit within the catheter 301 along withthe porous membranes 304 a,304 b, and filtration material 305.

In the embodiment shown, the filtering component includes a porous framestructure 303 (e.g., mesh), the two porous membranes 304 a,304 b, andfiltration material 305. When the frame structure 303 is expanded, thefiltering component is conical shaped or otherwise tapered. After theblood 351 and therapeutic agent (e.g., non-chemotherapeutic agent orchemotherapeutic agent, such as Dox) are administered upstream from atarget tissue site and eventually contact with the target tissue site,the blood 351 and therapeutic agent then flow into the distal end of thefiltering component and contact the porous membranes 304 a,304 b andfiltration material 305. The blood 351 passes through the porous framestructure 303 (e.g., mesh), two porous membranes 304 a,304 b, andfiltration material 305, while the therapeutic agent is filtered by thefiltration material 305.

It should be appreciated that the frame structure 303 may be part of thecatheter 101 or independently positioned within catheter 101.Furthermore, the elongated control member 307, membranes 304 a, 304 band filtration material 305 may be part of the frame structure 303 orremovably coupled to the frame structure, or independently positionedwithin the catheter 101 and frame structure 303. In this way, theelongated member 307, membranes 304 a,304 b, and filtration material 305may be introduced within catheter 301 and frame structure 303 andthereafter removed (e.g., for continuous replacement during theprocedure) while the catheter 301 and/or frame structure 303 remainspositioned within the blood vessel. It should be appreciated that thismay also be applicable to the other example embodiments shown in thefigures.

FIG. 4 illustrates an example filtration device, according to oneembodiment. Filtration device 400 includes an elongated control member407 that is operably coupled to a frame structure 403. Frame structure403 is coupled to two porous membranes 404 a,404 b that have filtrationmaterial 405 disposed between the two porous membranes 404 a,404 b.

The elongated control member 407 is operably coupled to the framestructure 403 and is used to displace the frame structure 405, porousmembranes 404 a,404 b, and filtration material 405 horizontally alongthe central axis of the catheter 401. The frame structure 403 is biasedto an expanded state so that when the frame structure 403 is displacedoutside the distal end of the catheter 401, as shown, the framestructure 403 is expanded to occupy the cross sectional area of theblood vessel 450. The frame structure 403 is constrainable such thatwhen the frame structure 403 is drawn within the distal end of catheter401, the frame structure 403 constrains to fit within the catheter 401along with the porous membranes 404 a,404 b, and filtration material405.

In the embodiment shown, the filtering component includes a porous framestructure 403 (e.g., mesh), the two porous membranes 404 a,404 b, andfiltration material 405. The membranes 404 a,404 b are folded orotherwise shaped in an uneven manner to increase the surface area of themembranes 404 a,404 b that contacts the blood 451 and therapeutic agent.When the frame structure 403 is expanded, the filtering component isconical shaped or otherwise tapered. After the blood and therapeuticagent (e.g., non-chemotherapeutic agent or chemotherapeutic agent, suchas Dox) are administered upstream from a target tissue site andeventually contact with the target tissue site, the blood 451 andtherapeutic agent then flow into the distal end of the filteringcomponent and contact the porous membranes 404 a,404 b and filtrationmaterial 405. The blood 451 passes through the porous frame structure403 (e.g., mesh), two porous membranes 404 a,404 b, and filtrationmaterial 405, while the therapeutic agent is filtered by the filtrationmaterial 405.

FIG. 5 illustrates an example filtration device, according to oneembodiment. Filtration device 500 includes an elongated control member507 that is operably coupled to a frame structure 503. Frame structure503 is coupled to two porous membranes 504 a,504 b. Instead of havingfiltration material disposed between the two membranes 504 a,504 b, themembranes 504 a,504 b are composed of a filtration material that filtersthe therapeutic agent. For example, membranes 504 a,504 b may becomposed of resin or carbon material, or may be made from a materialthat is impregnated with a filtration material having adsorptive,binding, or catalytic properties. In another embodiment, a singlemembrane composed of the filtration material is disposed on the framestructure 503.

The elongated control member 507 is operably coupled to the framestructure 503 and is used to displace the frame structure 505 and porousmembranes 504 a,504 b horizontally along the central axis of thecatheter 501. The frame structure 503 is biased to an expanded state sothat when the frame structure 503 is displaced outside the distal end ofthe catheter 501, as shown, the frame structure 503 is expanded tooccupy the cross sectional area of the blood vessel 550. The framestructure 503 is constrainable such that when the frame structure 503 isdrawn within the distal end of catheter 501, the frame structure 503constrains to fit within the catheter 501 along with the porousmembranes 504 a,504 b containing the filtration material.

In the embodiment shown, the filtering component includes the porousframe structure 503 (e.g., mesh) and the two porous membranes 504 a,504b composed of the filtration material. When the frame structure 503 isexpanded, the filtering component is conical shaped or otherwisetapered. After the blood 551 and therapeutic agent (e.g.,non-chemotherapeutic agent or chemotherapeutic agent such as Dox) areadministered upstream from a target tissue site and eventually contactwith the target tissue site, the blood 551 and therapeutic agent thenflow into the distal end of the filtering component and contact theporous membranes 504 a,504 b composed of the filtration material. Theblood 551 passes through the porous frame structure 503 (e.g., mesh) andtwo porous membranes 504 a,504 b composed of the filtration material,while the therapeutic agent is filtered by the membranes 504 a,504 bcomposed of the filtration material.

FIG. 6 illustrates an example filtration device, according to oneembodiment. Filtration device 600 includes an elongated control member607 that is operably coupled to a frame structure 603. Frame structure603 is coupled to a structure of filtration elements 604 made of afiltration material that filters the therapeutic agent. The structure ofelements 604 may have any variety of shapes, sizes, and densities. Forexample, each of the filtration elements of the structure 604 may belinear members (e.g., resembling bristles on a brushes), non-linearmembers, sheets or membranes, etc. The structure of filtration elements604 may, for example, be composed of a filtration material havingadsorptive, binding, or catalytic properties (e.g., resin, carbon,catalytic material, etc.), or may be made from a material that isimpregnated with a filtration material (e.g., particles) having suchadsorptive, binding, or catalytic properties.

The structure of filtration elements 604 may have any variety of threedimensionally shaped configurations that provide increased filtering asblood and therapeutic agents enter further into the structure ofelements 604. The structure may include varying patterns (e.g., regularor irregular patterns), sizes and thicknesses In certain embodiments,the structure 604 may be constructed of one or more thick layers ofporous membrane, or multiple densely packed filtration elements (e.g.,linear members, porous membranes, etc.) to resemble a sponge-likestructure.

In another embodiment, the structure 604 may be constructed withfiltration elements extending from a central axis member 608 to theframe structure 603. In some instances, the central axis member 608 isthe elongated control member 607 or extension therefrom. The pattern ofthe filtration elements 604 may vary, and may include any regular orirregular patterns. For instance, in one embodiment, the porousmembranes extend radially outward from the central axis member 608towards the frame structure 608 to resemble a pipe-brush configuration.In yet another embodiment, the structure 604 may be constructed withtiny resin beads being attached together (e.g., in a linear arrayconnected with a thin wire). That string would have high surface areaand could be introduced and removed easily.

The elongated control member 607 is operably coupled to the framestructure 603 and is used to displace the frame structure 605 and thestructure of filtration elements 604 horizontally along the central axisof the catheter 601. The frame structure 603 is biased to an expandedstate so that when the frame structure 603 is displaced outside thedistal end of the catheter 601, as shown, the frame structure 603 isexpanded to occupy the cross sectional area of the blood vessel 650. Theframe structure 603 is constrainable such that when the frame structure603 is drawn within the distal end of catheter 601, the frame structure603 constrains to fit within the catheter 601 along with the structureof filtration elements 604 composed of a filtration material.

In the embodiment shown, the filtering component includes the porousframe structure 603 (e.g., mesh) and the structure of filtrationelements 604 containing the filtration material. When the framestructure 603 is expanded, the frame structure 603 is conical shaped orotherwise tapered. After the blood 651 and therapeutic agent (e.g.,non-chemotherapeutic agent or chemotherapeutic agent such as Dox) areadministered upstream from a target tissue site and eventually contactwith the target tissue site, the blood and therapeutic agent then flowinto the distal end of the filtering component and contact the structureof filtration elements 604 composed of the filtration material. Theblood 651 passes through the porous frame structure 503 (e.g., mesh) andstructure of filtration elements 604 composed of the filtrationmaterial, while the therapeutic agent is filtered by the structure offiltration elements 604 composed of the filtration material.

FIG. 7 illustrates an example filtration device, according to oneembodiment. Filtration device 700 includes an elongated control member(not shown) that is operably coupled to a frame structure 703. Theelongated control member is operably coupled to the frame structure 703and is used to displace the frame structure 705 horizontally along thecentral axis of the catheter 701. The frame structure 703 is biased toan expanded state so that when the frame structure 703 is displacedoutside the distal end of the catheter 701, as shown, the framestructure 703 is expanded to occupy the cross sectional area of theblood vessel 750. The frame structure 703 is constrainable such thatwhen the frame structure 703 is drawn within the distal end of catheter701, the frame structure 703 constrains to fit within the catheter 701.

Instead of having filtration material disposed on the frame structure703, the filtration material 705 is disposed within a lumen of thecatheter 701. For example, in one embodiment, the filtration materialmay be pre-packed within the lumen of the catheter 701. In someinstances, the filtration material may be removable and replaceable,such as by a wire attached to the filtration material or by removing orreplacing a pre-packed filtration cartridge that fits within the lumenof the catheter. In one embodiment, filtration material 705 may bedisposed on the elongated control member extending along the centralaxis of the catheter 701. In some instances, the filtration material 705may be removable and replaceable by the elongated control member. Inanother embodiment, the filtration material may be disposed around theelongated control member. In certain embodiments, the filtrationmaterial includes resin or carbon material, or other filtration materialhaving adsorptive, binding, or catalytic properties.

The catheter 701 includes holes 709 that permit the blood to passthrough from the lumen of the catheter 701 to the blood vessel 750. Insome instances, the holes 709 may be sized to be smaller than the sizeof the particles of the filtration material. For example, the filtrationmaterial may include beads having properties that absorb, bind, orinactivate or degrade the therapeutic agent, and the holes sized smallerthan the size of the beads.

In the embodiment shown, the filtering component includes filtrationmaterial 705 and holes 709. When the non-porous frame structure 703 isexpanded, the frame structure 703 is conical shaped or otherwise taperedto direct blood 751 and therapeutic agent into the lumen of the catheter701. After the blood and therapeutic agent (e.g., non-chemotherapeuticagent or chemotherapeutic agent such as Dox) are administered upstreamfrom a target tissue site and eventually contact with the target tissuesite, the blood and therapeutic agent then flow into the distal end ofthe frame structure 703 and directed to the lumen of the catheter 701 tocome into contact with the filtration material 705 disposed within thelumen of the catheter. The blood 751 passes by or through the filtrationmaterial 705 and out the holes 709 of the catheter 701, while thetherapeutic agent is filtered by the filtration material 705.

FIG. 8 illustrates an example filtration device, according to oneembodiment. Filtration device 800 includes an inflatable balloon 810that is disposed on frame structure 803 at the distal end of thecatheter 801. In the embodiment shown, the frame structure 803 is thedistal portion of the catheter 801. In another embodiment, the framestructure 803 may be a separate element coupled to the catheter 801.

The inflatable balloon 810 is disposed at the distal end of catheter 801and may be deflated when the filtration device is being positionedwithin the blood vessel, and then inflated when positioned at the targetsite downstream from the target tissue. The term “balloon” is usedbroadly herein to refer to any type of chamber, container, etc., thatcan fill with air or fluid and expand.

When inflated, the balloon 810 occupies the cross sectional area of theblood vessel 850 to obstruct the blood flow in blood vessel and directit into the distal end of the lumen of the catheter 801.

Filtration material 805 is disposed within the lumen of the catheter801, as similarly described for FIG. 7. For example, the filtrationmaterial 805 may be disposed on or around an elongated control memberextending along the central axis of the catheter 801. The elongatedcontrol member may be used, for example, to position the inflatableballoon 810 and to add or remove air or fluid to inflate or deflate theballoon 810, respectively. In certain embodiments, the filtrationmaterial 805 includes resin or carbon material, or other filtrationmaterial having adsorptive, binding, or catalytic properties.

The catheter 801 includes holes 809 that permit the blood to passthrough from the lumen of the catheter 801 to the blood vessel 850, assimilarly described for FIG. 7. In the embodiment shown, when theinflatable balloon 810 is inflated, the balloon 810 occupies the crosssectional area of the blood vessel 850 to obstruct the blood flow inblood vessel and direct it into the distal end of the lumen of thecatheter 801.

In the embodiment shown, the filtering component includes filtrationmaterial 805 and holes 809. After the blood 851 and therapeutic agent(e.g., non-chemotherapeutic agent or chemotherapeutic agent such as Dox)are administered upstream from a target tissue site and eventuallycontact with the target tissue site, the blood and therapeutic agent arethen obstructed by the inflatable balloon 810 and directed into thedistal end of the lumen of the catheter 801 and directed to the lumen ofthe catheter 801 to come into contact with the filtration material 805disposed within the lumen of the catheter 801. The blood 851 passes byor through the filtration material 805 and out the holes 809 of thecatheter 801, while the therapeutic agent is filtered by the filtrationmaterial 805.

FIG. 9 illustrates an example filtration device, according to oneembodiment. Filtration device 900 includes an elongated control member907 that is operably coupled to porous membranes 904 a, 904 b, alsofunctioning as the frame structure in this embodiments. Membranes 904 a,904 b have filtration material 905 disposed between the two porousmembranes 904 a, 904 b.

The elongated control member 907 is operably coupled to the porousmembranes 904 a, 904 b and is used to displace the porous membranes 904a, 904 b and filtration material 905 horizontally along the central axisof the catheter 301. The porous membranes 904 a, 904 b are biased to anexpanded state so that when the porous membranes 904 a, 904 b aredisplaced outside the distal end of the catheter 901, as shown, theporous membranes 904 a, 904 b are expanded to occupy the cross sectionalarea of the blood vessel 950. In the embodiment shown, the porousmembranes 904 a, 904 b are shaped to direct blood flow away from theradial center of the vessel—e.g., conically shaped to decrease in crosssectional size towards the distal end. The widest cross section area ofmembranes 904 a,904 b at the proximal end of the membranes 904 a,904 boccupies the cross sectional area of the blood vessel 950 when themembranes 904 a, 904 b are expanded.

The membranes 904 a, 904 b are constrainable such that when themembranes 904 a, 904 b is drawn within the distal end of catheter 901via the elongated control member 907, the membranes 904 a, 904 bconstrains to fit within the catheter 301 along with the filtrationmaterial 905. The term “constrain” is used broadly herein and mayinclude constricting, contracting, compressing, bending, or otherwisealtering the material or element to become narrower, such as to fitwithin the lumen of the catheter when constrained and to expand in sizeto occupy the blood vessel when outside the catheter. In the embodimentshown, the elongated control member 907 may be used to pull themembranes 904 a, 904 b back into the distal end of the catheter 901 bybending and compressing the conical membranes 904 a, 904 b as it isdrawn into the catheter 901, for example.

In the embodiment shown, the filtering component includes membranes 904a, 904 b and filtration material 905. When the membranes 904 a, 904 bare expanded, the membranes 904 a, 904 b are conical shaped to directblood flow away from the radial center of the vessel. After the bloodand therapeutic agent (e.g., non-chemotherapeutic agent orchemotherapeutic agent, such as Dox) are administered upstream from atarget tissue site and eventually contact with the target tissue site,the blood 951 and therapeutic agent then flow to the distal end of thefiltering component and contact the porous membranes 904 a, 904 b andfiltration material 905. The blood 951 is directed away from the radialcenter of the blood vessel, eventually passing through the porousmembranes 904 a, 904 b and filtration material 905, while thetherapeutic agent is filtered by the filtration material 305.

FIG. 10 illustrates an example filtration device, according to oneembodiment. Filtration device 1000 includes an elongated control member1007 that is operably coupled to porous membranes 1004 a, 1004 b, alsofunctioning as the frame structure in this embodiments. Membranes 1004a,1004 b have filtration material 1005 disposed between the two porousmembranes 1004 a, 1004 b.

The elongated control member 1007 is operably coupled to the porousmembranes 1004 a, 1004 b and is used to displace the porous membranes1004 a, 1004 b and filtration material 1005 horizontally along thecentral axis of the catheter 1001. The porous membranes 1004 a, 1004 bare biased to an expanded state so that when the porous membranes 1004a, 1004 b are displaced outside the distal end of the catheter 1001, asshown, the porous membranes 1004 a, 1004 b are expanded to occupy thecross sectional area of the blood vessel 1050. In the embodiment shown,the porous membranes 1004 a, 1004 b are shaped to increase and thendecrease in cross-sectional area from the distal end towards theproximal end. At the widest cross sectional area of membranes 1004 a,1004 b, the membranes 1004 a, 1004 b occupies the cross sectional areaof the blood vessel 1050 when the membranes 1004 a, 1004 b are expanded.

The membranes 1004 a, 1004 b are constrainable such that when themembranes 1004 a, 1004 b are drawn within the distal end of catheter1001 via the elongated control member 1007, the membranes 1004 a, 1004 bconstrains to fit within the catheter 1001 along with the filtrationmaterial 1005. In the embodiment shown, the elongated control member1007 may be used to pull the membranes 1004 a, 1004 b back into thedistal end of the catheter 1001 by constraining the conical membranes1004 a, 1004 b as it is drawn into the catheter 1001, for example.

In the embodiment shown, the filtering component includes membranes 1004a, 1004 b and filtration material 1005. When the membranes 1004 a, 1004b are expanded, the distal side of membranes 1004 a, 1004 b are conicalshaped to direct blood flow away from the radial center of the vessel.After the blood and therapeutic agent (e.g., non-chemotherapeutic agentor chemotherapeutic agent, such as Dox) are administered upstream from atarget tissue site and eventually contact with the target tissue site,the blood and therapeutic agent then flow to the distal end of thefiltering component and contact the porous membranes 1004 a, 1004 b andfiltration material 1005. The blood 1051 is directed away from theradial center of the blood vessel, eventually passing through the distalside of the porous membranes 1004 a, 1004 b and filtration material1005, and then again passing through the proximal side of the porousmembranes 1004 a, 1004 b and filtration material 1005, which taperstowards the radial center of the blood vessel. Similarly, thetherapeutic agent is filtered by the filtration material 1005 as itpasses contacts the distal side of the porous membranes 1004 a, 1004 band filtration material 1005. Any therapeutic agent that passes throughthe distal side of the porous membranes 1004 a, 1004 b without beingfiltered by the filtration material 1005, will then contact the proximalside of the porous membranes 1004 a, 1004 b and filtered by thefiltration material 1005.

The filtration devices shown in FIGS. 3-10 are exemplary and may vary inconfiguration in other embodiments, such as to include featuresdescribed in other parts of the present disclosure. In certainembodiments, the filtration material may include one or more types ofmaterial having properties that adsorb, bind, or inactivate or degradeone or more therapeutic agents, and each may be eithernon-chemotherapeutic or chemotherapeutic, independent of the other. Incertain embodiment, the filtration material adsorbs and/or chemicallybinds to the therapeutic agent. For example, the filtration material mayinclude a resin or activated carbon having properties to adsorb and/orchemically bind to the therapeutic agent, and/or magnetically bind to amagnetic carrier bound to the therapeutic agent. The therapeutic agentmay include doxorubicin, for example, and the filtration material mayinclude, but is not limited to: strong acid cation exchange polymerresins; ion exchange resins; polymeric adsorbent resins without ionexchange; resins including sulfonate groups that ionically bond to thetherapeutic agent; chromatography based resins, or any combinationthereof. In certain embodiments, the filtration material may include amaterial that inactivates or degrades the therapeutic agent. Forexample, the filtration material may include a catalytic material thatenzymatically degrades a therapeutic agent, such as Dox. In oneembodiment, the filtration material may include a material that adsorband/or chemically bind to the therapeutic agent and that inactivates ordegrades the therapeutic agent. In certain embodiments, the filtrationmaterial may include a material that improves biocompatibility, such aspolymethyl-methacrylate (PMMA), chitosan, heparin, etc. In someinstances, for example, the resin or carbon may be coated or otherwiseimpregnated with the PMMA, chitosan, and/or heparin. Furthermore, asexplained in other parts of the present disclosure, in some instances,the catheter may be integrated with the filtration device. In otherinstances, the filtration device may be removable and replaceable duringuse, such as with the catheter is still within the blood vessel. In someinstances, the catheter includes the filtration device within its lumenwhen the catheter is being positioned in the blood vessel. In otherinstances, the filtration device may be inserted into the lumen of thecatheter after the catheter is positioned in the blood vessel.

Methods

In some aspects of the present disclosure, methods of in vivo filtrationof one or more therapeutic agents are provided. The methods includepositioning a filtration device in a blood vessel of a body of a humanor non-human animal, and administering a therapeutic agent upstream fromthe target tissue site to direct flow of the therapeutic agent to thetarget tissue site and then to the filtration device. The filtrationdevice is positioned downstream from a target tissue site. Further, thefiltration device is for filtering the therapeutic agent in the bloodflowing in the blood vessel. The in vivo positioned filtration devicefilters the therapeutic agent as the blood and the therapeutic agent arereceived by the filtration device. Various examples of positioneddevices in different blood vessels are depicted in FIGS. 14A-14J,including the hepatic vein (FIGS. 14A-14B), iliac vein (FIGS. 14C-14D),inferior vena cava (FIG. 14E), renal vein (FIGS. 14F-14G), and superiorvena cava (FIGS. 14H-14L). Additional exemplary positioning of thepresent device also include, but are not limited to, intracranially inthe dural venous sinuses (e.g., sigmoid sinus, transverse sinus,torcula, straight sinus, superior sagittal sinus) to remove agentsduring cerebral embolization or chemoinfusion; internal jugular veinwith the device inserted, for example, either transfemorally or directlyin the ipsilateral internal jugular vein, for head and neck tumors andduring cerebral embolization or chemoinfusions; and the brachiocephalicvein between the superior vena cava and the internal jugular vein.

It should be appreciated that the methods may include the filtrationdevices described in the present disclosure, and for the sake of clarityand brevity, will not be described in great detail again, but ratherreference is made to the previous discussion of these features.Additionally, the description of the methods of using the filtrationdevices is also applicable to the methods section, and will not bedescribed again great detail again but rather reference is made to theprevious discussion.

The target tissue may include, for example, cancerous or otherwisediseased tissue. The target tissue site should be accessible by thebloodstream and may include organs for instance. Example canceroustissue sites may include, but are not limited to the liver, kidney,brain, head/neck, skin gastrointestinal tract, and musculoskeletalsystem. For example, the target tissue site may include an organafflicted with cancerous growths.

The therapeutic agent is administered upstream from the target tissuesite—e.g., intraarterially or intravenously supplying a cancerous orotherwise diseased organ. In certain embodiments, the filtration deviceis positioned within a vein draining a target organ—e.g., an organcontaining diseased or cancerous tissue—or a central vein. In someinstances, for example, the filtration device may be inserted within aninternal jugular or femoral vein. In some instances, the filtrationdevice may be malleable to conform to the vein, such as the renal vein,hepatic vein, or vena cavae.

The distance the filtration device is positioned from the target tissuesite may vary based on the particular blood vessel, the location of thetarget tissue site (e.g., which organ), etc. The distance to the targettissue site or organ including the target tissue may vary. For instance,example distances may include, but are not limited to, distances fromtwo feet or less, such as 6 inches or less, including three inches orless. In one embodiment, the distance may be less than one inch from thetarget tissue site or organ including the target tissue. In otherembodiments, the distance to the target tissue site or organ may begreater than two feet, such as up to four feet—e.g., if for instance, atumor was present in person's extremity such as a toe and the filtrationdevice placed in the inferior vena cava. It should be appreciated thatthe ranges are exemplary, and distances outside the example rangesprovided are also possible.

In certain embodiments, the filtration device may be positioned in theblood vessel by inserting a catheter within the blood vessel downstreamfrom the target tissue. In one embodiment, the filtration device ispositioned within the catheter at the time the catheter is insertedwithin the blood vessel. In another embodiment, the catheter is firstinserted within the blood vessel, and thereafter the filtration deviceis inserted within the lumen of the catheter. When inside the catheter,an elongated control member may be used by the operator to displace thefiltration device within the lumen of the catheter until a portion ofthe filtration device is displaced out the distal end of the catheterand into the blood vessel. The filtration device may include a framestructure that expands to occupy the entire cross sectional area of theblood vessel when the frame structure is displaced out the distal end ofthe catheter. The elongated control member may also be used by theoperator to retract and constrain the exposed portion of the filtrationdevice back inside the catheter.

In certain embodiments, the filtration device is removable from thecatheter during use—e.g., while the catheter is still positioned insidethe blood vessel. In some instances, the filtration device may besterilized and reusable. In other instances, the filtration device maybe disposable and a replacement filtration device may be inserted intothe catheter after the original filtration device is discarded. Thereplacement filtration device is then displaced within the catheteruntil a portion of the replacement filtration device is displaced outthe distal end of the catheter, and the filtration process repeated withthe replacement filtration device.

It should be appreciated that the frame structure may be part of thecatheter or independently positioned within catheter. Furthermore, theelongated control member, membranes, and filtration material, may bepart of the frame structure or removably coupled to the frame structure,or independently positioned within the catheter and frame structure. Inthis way, the elongated member, membranes, and filtration material maybe introduced within catheter and frame structure and thereafter removed(e.g., for continuous replacement during the procedure) while thecatheter and/or frame structure remains positioned within the bloodvessel.

After the filtering of the therapeutic agent is complete, the cathetermay be removed from the blood vessel. In one embodiment, the filtrationdevice is removed before the catheter. In another embodiment, thecatheter is removed from the blood vessel while the filtration device iswithin the catheter. It should also be appreciated that in certainembodiments, the filter component is left within the blood vessel whilethe catheter is removed from the blood vessel. At a later time (e.g.,days, weeks, months, etc.) the filter may be removed—e.g., with a snarecatheter for instance. It is also appreciated that filters may be usedand/or replaced during the procedure, with a filter remaining in theblood vessel after the procedure for removal at a later time.

The therapeutic agent may include, for example, any variety of agents,such as drugs or chemical substances used in the treatment, cure,prevention, or diagnosis of disease or used to otherwise enhancephysical or mental well-being. The therapeutic agent may include, forexample, chemotherapeutic agents and/or non-chemotherapeutic agents. Inone embodiment, the therapeutic agent is Dox and used to treat canceroustissue, such as within an organ. Non-chemotherapeutic agents mayinclude, but are not limited to, for example, anti-coagulants,thrombolytics, etc. The thrombolytic may be used, for example, in stroketreatment.

It will be appreciated that in certain embodiments, the therapeutic gentadministered to the subject is known to be therapeutically beneficialabove a certain concentration level in the blood. After a certain timeonce the concentration decreases below a specific threshold, it is onlyprimarily toxicity that the patient receives. In such embodiments, thepresent device may be placed intraarterially or intravenously at thetime when the concentration drops below that agent's therapeutic levelin order to filter the agent and prevent toxicity. It will beappreciated buy one of skill in the art that this timing may bederivable from published known in vivo kinetics/clearance profile of thetherapeutic agent.

Example

FIG. 11 shows an in-vitro experimental flow model used to test theefficacy of various carbons and resins. Flow model 1100 is shownincluding a filter circuit with resin 1101, digital flow meter 1102,voltage drive fluid pump 1103, and container containing Dox solution1105 coupled to one another via polymer tubing. The container of Doxsolution 1105 is heated by heating element 1104.

The designed flow model simulates intraarterial chemotherapy delivery byemploying a voltage governed fluid pump 1103 and digital flow meter1102, which can control flow rate to match the renal vein (.about.750ml/min). The dimensions of the polymer tubing used also matched that ofan average renal vein, with filter segment measuring 6 cm in length and1.2 cm in diameter (34). A 1 liter solution of phosphate bufferedsolution (PBS) S) with Ca2+ and Mg2+ is warmed and mixed to 37.degree.C., thereby simulating a physiologic environment with serumelectrolytes, pH, and temperature. A solution of concentrated 2 mg/mlDox HCl is introduced into the system via injection ports to bring theoverall solution Dox concentration to approximately 0.05 mg/ml (50 mgtotal drug, similar to a dose administered in transarterialchemoembolization (TACE). The filter column is filled with adsorbentmaterial to a volume matching that of a cone in the renal vein (2.26ml). The adsorbent materials are contained in the filter circuit by a200-micron mesh filter (particles are greater than this size). A 200micron size was selected since prior studies of carotid protectiondevices demonstrate this pore size to allow free passage of bloodproducts with minimal pressure drops (35). Samples were taken from theflow model system for the next 1-4 hours, and Dox concentrationsmeasured via UV spectrophotometry at its known peak wavelength of 480nm.

During extensive initial research of candidate compounds, nine materialswere tested. Given interest in rapid high capacity drug binding, ametric referred to herein as TACE Factor (TF), was measured as total Doxbound during the first 10 minutes per ml of adsorbent with a goal TFbeing approximately 10 given a 2.5 ml constraint and aim to bind 25 mgof drug. One resin in particular, a macroporous strong acid ion-exchangeresin with a hydrophilic polyvinyl backbone, demonstrated excellentresults with a TF of 19 and rapid time to equilibrium essentially at 20minutes. This is represented in the graph 1100 of FIG. 12, showing plots1203 of Dox absorbed over time, with milligrams of Dox along axis 1201and time in minutes along axis 1202. Biorad AG50W-X2 resin (e.g.,200-400 mesh) was used. 73% (49 or 67 mg Dox) was absorbed at 10 mins. ATF of 19 achieved. A generic equivalent resin, Dowex 50W-X2 (200-400mesh) provided similar results. Another macroporous adsorbent resinwithout ion-exchange properties, also demonstrated similar results witha dramatic three-fold decrease in drug concentration over 60 minutes.This is represented in the graph 1300 of FIG. 13, showing plots 1303 ofDox concentration over time, with mg/ml of Dox shown along axis 1301 andtime in minutes along axis 1302.

Preliminary device prototypes were also constructed a large stent deviceas well as a carotid protection filter. For instance, a partiallydeployed stent with 200-micron double mesh lining sandwiching adsorbentmaterial. When deployed from its sheath within the selected vein, it hasa conical shape or wind-sock like shape, with volume approximating thatof a cone fitting within the renal vein (dimensions 6 cm length, 1.2 cmdiameter).

Although the foregoing embodiments have been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of the present disclosure that certainchanges and modifications may be made thereto without departing from thespirit or scope of the appended claims. It is also to be understood thatthe terminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein.

We claim:
 1. A method for filtering one or more one or morechemotherapeutic agents in blood flowing in a blood vessel within apatient, comprising: introducing a distal end of an elongate membercarrying a filtering component into a blood vessel downstream from atarget tissue site; deploying the filtering component within the bloodvessel, the filtering component comprising a porous membrane including aproximal end and a distal end and configured such that blood flowingthrough the blood vessel passes through an interior of the filteringcomponent; and administering a chemotherapeutic agent upstream from thetarget tissue site to direct flow of the chemotherapeutic agent to thetarget tissue site and then to the filtering component, wherein thefiltering component comprises filtration material disposed within theporous membrane configured to bind or adsorb the chemotherapeutic agentas the blood flows through the interior.
 2. The method of claim 1,wherein the porous membrane is shaped to increase and then decrease incross-sectional area from the distal end to the proximal end.
 3. Themethod of claim 1, wherein the porous membrane is expandable to occupy across sectional area of the vein within which the porous membrane isdeployed.
 4. The method of claim 1, wherein the target tissue site iswithin the patient's kidney or liver.
 5. The method of claim 1, whereinthe blood vessel is a renal or hepatic vein.
 6. The method of claim 1,wherein the filtration material comprises a plurality of beadscomprising a resin that adsorbs the chemotherapeutic agent.
 7. Themethod of claim 1, wherein the filtration material comprises a pluralityof beads comprising a resin that chemically binds the chemotherapeuticagent.
 8. The method of claim 1, wherein the filtration materialcomprises a plurality of beads comprising an ion exchange resin.
 9. Themethod of claim 1, wherein the filtration material comprises a pluralityof beads comprising a strong acid cation polymer resin.
 10. The methodof claim 1, wherein the filtration material is coated with heparin,polymethyl-methacrylate, or chitosan.
 11. A method for filtering one ormore one or more chemotherapeutic agents in blood flowing in a bloodvessel within a patient, comprising: introducing a distal end of anelongate member carrying a filtering component into a blood vesseldownstream from a target tissue site; expanding the filtering componentwithin the blood vessel, the filtering component comprising a porousmembrane including a proximal end and a distal end, the porous membraneexpanding within a blood vessel such that blood flowing through theblood vessel passes into the distal end through an interior of thefiltering component and out the proximal end; and administering achemotherapeutic agent upstream from the target tissue site to directflow of the chemotherapeutic agent to the target tissue site and then tothe filtering component, wherein the filtering component comprisesfiltration material disposed within the porous membrane configured tobind the chemotherapeutic agent as the blood flows through the interior.12. The method of claim 11, wherein the porous membrane is shaped toincrease and then decrease in cross-sectional area from the distal endto the proximal end.
 13. The method of claim 11, wherein thechemotherapeutic agent is doxorubicin.
 14. The method of claim 11,wherein the target tissue site is within the patient's kidney or liver.15. The method of claim 11, wherein the blood vessel is a renal orhepatic vein.
 16. The method of claim 11, wherein the filtrationmaterial comprises a plurality of beads comprising a resin that adsorbsthe chemotherapeutic agent.
 17. The method of claim 11, wherein thefiltration material comprises a plurality of beads comprising a resinthat chemically binds the chemotherapeutic agent.
 18. The method ofclaim 11, wherein the filtration material comprises a plurality of beadscomprising an ion exchange resin.
 19. The method of claim 11, whereinthe filtration material comprises a plurality of beads comprising astrong acid cation polymer resin.
 20. The method of claim 11, whereinthe filtration material is coated with heparin, polymethyl-methacrylate,or chitosan.
 21. The method of claim 11, further comprising removing thefiltering component from the blood vessel while the elongate memberremains within the blood vessel.